PC-AssayDescription ::= {
aid {
id 651767,
version 1
},
aid-source db {
name "NCGC",
source-id str "WRN000"
},
name "qHTS for Inhibitors of WRN Helicase: Summary",
description {
"Inhibition of DNA repair is proposed as a strategy for combating cancer.
Synthetic lethality is an approach that exploits preexisting DNA repair
deficiencies in certain tumors to develop inhibitors of DNA repair pathways
that compensate for the tumor-associated DNA repair deficiency. Because
helicases play critical roles in the DNA damage response and in DNA repair,
particularly in actively dividing and replicating cells, characterization of
synthetic lethal relationships of DNA helicases may be of value in developing
improved anticancer treatment strategies; moreover, small molecules that
specifically target a given DNA helicase may be useful for understanding its
role in cellular nucleic acid metabolism. The goal of this project is to
identify small molecule, non-covalent chemical inhibitors of the Werner
syndrome (WS) helicase (WRN), which plays an important role in cell
proliferation, the replication stress response, and DNA repair. Werner
syndrome is a premature aging disorder that displays many clinical symptoms
of aging at an accelerated rate. The WRN gene product that is defective in
the chromosomal instability disorder has DNA helicase and exonuclease
activities and interacts with a number of nuclear proteins to maintain
genomic stability. ",
"",
"We will employ an optimized high-throughput screening assay that utilizes
a fluorescence intensity modulation scheme with a fluorophore and quencher
positioned near one another within a duplex deoxyoligonucleotide that
contains a single forked structure. After a high-throughput screen of the
~350,000-member Molecular Libraries Small Molecule Repository (MLSMR)
collection, followed by data analysis and hit selection, a panel of
confirmatory, as well as secondary and ternary, assays will be employed to
identify high-confidence WRN inhibitors. Structure-activity relationships
will be investigated for the top candidate inhibitor series through medchem
expansion. These are the results of the primary screening campaign against
the MLSMR.",
"",
"NIH Chemical Genomics Center [NCGC]",
"NIH Molecular Libraries Probe Centers Network [MLPCN]",
"",
"MLPCN Grant: MH096530",
"Assay Submitter (PI): Robert Brosh, National Institute of Aging"
},
protocol {
"Please see linked AIDs for detailed protocols."
},
comment {
"This project is ongoing and will be updated at a later point."
},
xref {
{
xref dburl "http://www.ncgc.nih.gov"
},
{
xref gene 7486
},
{
xref taxonomy 9606
}
},
revision 1,
target {
{
name "WRN [Homo sapiens]",
mol-id 3719421,
molecule-type protein,
organism {
org {
taxname "Homo sapiens",
common "human",
db {
{
db "taxon",
tag id 9606
}
}
}
}
}
},
activity-outcome-method summary,
grant-number {
"MH096530"
},
project-category mlpcn
}